Marked decreases in ionized magnesium levels occur during large volume leukapheresis, however, the role of magnesium supplementation has not been carefully studied in this setting. We performed a randomized, double-blind trial of intravenous magnesium sulfate administration in healthy allogeneic subjects undergoing peripheral blood progenitor cell (PBPC) donation. Thirty donors undergoing PBPC collection using standard citrate anticoagulant (ACD-A) and intravenous calcium prophylaxis were randomized to receive either intravenous magnesium (0.2 mg magnesium per mL ACD-A) or placebo during the apheresis procedure. Seventy-five PBPC procedures were evaluated in these 30 subjects, 38 using placebo and 37 using magnesium sulfate. Group characteristics were the same for gender (8 men and 7 women per group), weight (78 vs 81 kg), citrate infusion rate (1.36 vs 1.37 mg/kg/min), and volume processed (16 vs 17 liters). Serum ionized magnesium levels remained within the normal range with use of intravenous magnesium supplementation, but decreased to 39% below baseline with use of the placebo solution (p < 0.0001). Serum magnesium levels also decreased significantly following consecutive leukapheresis procedures in the placebo, but not the magnesium-treated donors. Subjects receiving magnesium showed significantly more vigorous parathyroid hormone responses and higher glucose levels, and also tended to have higher serum potassium and ionized calcium levels than subjects receiving placebo. Mild paresthesias, coldness, and nausea occurred in 28%, 20%, and 7% of donors, respectively, with no significant differences between groups. Severe citrate-related symptoms (chest tightness) occurred in only one subject during the study, a donor receiving placebo infusions. We conclude that intravenous magnesium supplementation exerts a significant impact on serum magnesium levels and other metabolic parameters during large volume leukapheresis, but that adverse clinical effects were rare in the presence of calcium prophylaxis. A much larger study would be required to detect small clinical differences attributable to magnesium infusions. The prior studies were performed in adult donors. In a separate study, we evaluated the use of high dose calcium and magnesium replacement in pediatric patients undergoing citrate-assisted apheresis, and compared outcomes to procedures in which heparin was used. Prophylactic magnesium administration was associated with preservation of serum magnesium levels but with no overall effect on donor symptoms. Pediatric patients frequently require placement of central venous devices, which may increase the risk of bleeding if systemic heparinization is used. Thus, citrate is the preferred anticoagulant in this setting. Since the acute decline in magnesium levels during citrate-assisted apheresis was very large in this pediatric population, our policy is to use both calcium and magnesium supplementation in pediatric subjects undergoing large volume leukapheresis.